GENETIC STUDIES OF CRANIOFACIAL AND LIMB DISORDERS

颅面和肢体疾病的遗传学研究

• 批准号: 6245362
• 负责人: Ethylin Wang Jabs
• 金额: $ 2.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-05 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6245362
• 关键词: autosomal dominant trait; clinical research; congenital skeletal disorder; congenital skin disorder; craniofacial dysostosis; craniosynostosis; family genetics; fibroblast growth factor; gene mutation; genetic disorder diagnosis; growth factor receptors; human subject; molecular pathology; neurogenetics; phenotype; receptor expression; syndrome; transposon /insertion element

Craniosynostosis, the premature fusion of calvarial sutures, is a common developmental anomaly that causes abnormal head shape. In moderate to severe cases, there is increase intracranial pressure and neurological sequelae, if not surgically treated. Craniosynostosis is a feature of as many as 50 genetic syndromes. Limb abnormalities, such as syndactyly and brachydactyly, are common associated features of these conditions. Crouzon, Jackson-Weiss, and Pfeiffer syndromes are autosomal dominant, craniosynostotic conditions with a wide variability of expression. We ascertained families with these conditions to study their chromosomes and/or DNA from established lymphoblastoid or fibroblast cell cultures. Fibroblast growth factor receptor 2 (FGFR2) mutations have been found in these conditions. We studied 39 cases with one of these three conditions for FGFR2 axon IlIa and llIc mutations. Eleven mutations were detected in 17 unrelated cases. Four mutations in either axon IlIa or axon llIc previously reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in axon IlIa in a Crouzon syndrome patient and the other in axon llIc in a Pfeiffer syndrome patient, were observed. The lafter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation, V359F, was detected in a family with one member with craniosynostosis and broad digits, diagnostic of Pfeiffer syndrome, and with two member with features consistent with Crouzon syndrome, craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders. We also studied a rare, autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, verrucous hyperplasia with hyperpigmentation of acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. We detected FGFR2 mutations in this condition, BeareStevenson cutis gyrata syndrome. Unlike the syndromes mentioned above, these mutations (Y375C and S372C) were found in axon 10 which contains the proximal region of or the transmembrane domain itself. These mutations presumably affect all FGFR2 isoforms, except soluble isoforms. Both the BEK (IIIc) and the keratinocyte growth factor receptor, KGFR (Illb) isoforms of FGFR2 formed by alternative splicing of exons lilc and lilb, respectively, would be affected because these exons are upstream of axon 10. The phenotype of Beare-Stevenson syndrome is consistent with the spatiotemporal expression patterns of both of these isoforms. The BEK isoform is expressed primarily in primordial bone and KGFR isoform predominantly in epithelial-derived tissues involved in the development of the skin.

颅缝早闭，即颅骨缝过早融合，是一种常见的疾病 导致头部形状异常的发育异常。 在中等至 严重者颅内压增高，神经系统功能障碍。 如果不进行手术治疗，会留下后遗症。 颅缝早闭是一个特征 多达50种遗传综合症。 肢体异常，例如并指 和短指，是这些病症的常见相关特征。 Crouzon、Jackson-Weiss 和 Pfeiffer 综合征为常染色体显性遗传， 颅缝早闭状况具有广泛的表达变异性。 我们 确定患有这些疾病的家庭来研究他们的染色体 和/或来自已建立的类淋巴母细胞或成纤维细胞培养物的DNA。 发现成纤维细胞生长因子受体 2 (FGFR2) 突变 在这些条件下。 我们研究了 39 例具有 FGFR2 轴突这三种情况之一的病例 IIIa和IIIc突变。 在 17 个不相关的个​​体中检测到 11 个突变 案例。 先前在轴突 IIIa 或轴突 IIIc 中发生四个突变 仅在克鲁宗综合征中报道，也存在于其他一种疾病中 两种综合症。 两次插入，一次位于克鲁宗综合征的轴突 IIIa 中 患者和另一位位于 Pfeiffer 综合征患者轴突 IIIc 中的患者，分别是 观察到。 后续突变具有相同的替代RNA剪接 作为已报道的克鲁宗综合征同义突变效应。 一个 在一个有一名成员患有此病的家庭中检测到错义突变 V359F 颅缝早闭和宽指，菲佛综合征的诊断，以及 有两名成员具有与克鲁宗综合征一致的特征， 颅缝早闭，无肢体异常。 家庭内部和家庭内部 FGFR2 突变表达的变异性表明这三种 被认为在临床上不同的综合征，实际上是 代表一系列相关的颅缝早闭和数字 失调。 我们还研究了一种罕见的常染色体显性遗传疾病，其特征是 回皮皱纹性皮肤病、疣状增生 黑棘皮症、颅缝早闭、 颅面畸形、指畸形、脐部和肛门生殖器畸形 异常和早逝。 我们检测到 FGFR2 突变 病情，BeareStevenson 皮肤回环综合征。 与综合症不同 如上所述，这些突变（Y375C 和 S372C）是在轴突中发现的 10 包含近端区域或跨膜结构域 本身。 这些突变可能影响所有 FGFR2 同工型，除了 可溶性异构体。 BEK (IIIc) 和角质形成细胞生长 因子受体，FGFR2的KGFR(IIIb)亚型由替代形成 外显子 lilc 和 lilb 的剪接分别会受到影响，因为 这些外显子位于轴突 10 的上游。 Beare-Stevenson 的表型 综合征与时空表达模式一致 这两种异构体。 BEK 同工型主要表达于 原始骨和 KGFR 亚型主要存在于上皮源性 参与皮肤发育的组织。